4-azatricyclo(4.3.1.13,8)undecan and related compounds

ABSTRACT

THIS INVENTION RELATES TO A NOVEL SERIES OF COMPOUNDS CHARACTERIZED PARTICULARLY BY THE AZATRICYCLO(4.3.1.1**3,8) UNDECANE RING. THESE INCLUDE 4-AZATRICYCLO(4.3.1.1**3,8) UNDECANE-5-ONE, 4-AZATICYCLO(4.3.1.1**3,8) UNDECANE AND NITROGEN SUBSTITUTED DERIVATIVES OF EACH OF THESE AND THEIR SALTS. THE COMPOUNDS ARE USEFUL AS ANTIVIRAL, CARDIOVASCULAR OR ANTINFLAMMATORY AGENTS, OR AS INTERMEDIATES FOR SUCH SUBSTANCES.

United States Patent 3,763,165 4-AZATRICYCLO[4.3.1.1 ]UNDECAN ANDRELATED COMPOUNDS Venkatchala Lakshima Narayuan, North Brunswick, and

Linda Louise Setescak, Cranbury, N.J., assignors to E. R. Squibb & Sons,Inc., New York, N.Y. No Drawing. Filed Aug. 21, 1968, Ser. No. 754,460Int. Cl. C07d 51/70 US. Cl. 260-268 PC 2 Claims ABSTRACT OF THEDISCLOSURE This invention relates to a novel series of compoundscharacterized particularly by the azatricyclo[4.3.1.1 ]undecane ring.These include 4-azatricyclo [4.3.1.1 ]undecan-S-one,4-azatricyclo[4.3.l.1 ]undecane and nitrogen substituted derivatives ofeach of these and their salts. The compounds are useful as antiviral,cardiovascular or antiinflarnmatory agents, or as intermediates for suchsubstances.

SUMMARY OF THE INVENTION This invention relates to the novelintermediate 4-azatricyclo[4.3.1.1 ]undecan-5-one (derived byrearrangement of 2-adamantane oXime) which may be depicted as follows:

R is hydrogen. The intermediate of Formula I may then either be reducedto 4-azatricyclo[4.3.1.1 ]undecane of the formula R being hydrogen, orreacted with a compound R--hal, in which R has the meaning defined belowother than hydrogen, to obtain a 4-azatricyclo[4.3.l.1 ]undecan-5- onederivative of the formula (III) R being other than hydrogen. Thecompound of Formula II may be reacted with a compound |R-hal, in which Ris other than hydrogen, or the compound of Formula III Patented Oct. 2,1973 "ice may be reduced, both reactions giving 4-azatricyclo [4.3.l.l]undecane derivatives of the formula The symbol R used above representshydrogen, lower alkyl, lower alkenyl, cycloalkyl-lower alkyl, thecycloalkyl group having 3 to 7 carbon atoms, aralkyl,

group in which the latter group represents a 5- to 7-mem: beredsaturated nitrogen heterocyclic, the R and R joining with the nitrogento form the heterocyclic, for example, pyrrolidino, piperidino,homopiperidino, piperazino, morpholino or thiamorpholino. In addition,the heterocyclic may bear one or two groups such as lower alkyl, loweralkoxy, halo, trihalomethyl, lower alkanoyloXy-lower alkyl orhydroxyl-lower alkyl.

The lower alkyl groups represented by the symbols include straight andbranched chain saturated hydrocarbon radicals of less than 8 carbonatoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl or the like and the lower alkenyl groups include similarmonounsaturated groups such as vinyl, allyl, isopropenyl, butenyl,isobutenyl, etc. The cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. These are attached to loweralkyl groups of the type described. The aralkyl groups are primarilyphenyl-lower alkyl groups in which the phenyl may be substituted by oneor two halogen atoms, which may be any of the four halogens butespecially chlorine or bromine, lower alkyl groups such as thoseenumerated above or lower alkoxy groups such as methoxy, ethoxy, propoxyor the like.

The symbols R and R in the group may be the same or diiferentrepresenting hydrogen, lower alkyl or hydroxy-lower alkyl groups such asthose referred to above. Illustrative of the group are amino,methylamino, ethylamino, dimethylamino, diethylamino, dipropylamino,methyl(ethyl)amino, di(hydroxyethyl)amino and the like.

group may also form a heterocyclic radical. The symbols R and R maytogether represent the carbon (and hydrogen) and the oxygen, sulfur ornitrogen atoms which, with the nitrogen atom in the above group, form a5-, 6- or 7-membered nitrogen heterocyclic containing not more than onehetero atom in addition to the nitrogen already shown in the group.These heterocyclic radicals may also bear one to three of the followingsubstituents: halogen, trifluoromethyl, lower alkoxy, lower alkyl,hydroxy-lower alkyl such as hydroxymethyl, Z-hydroxyethyl or the like,hydroxy-lower alkoxy-lower alkyl such as 2-(2-l1ydroxyethoxy)ethyl orthe like, alkanoyloxy-lower alkyl (up to about 14 carbons in thealkanoyl group) such as 2-heptanoyloxyethyl, carbo-lower alkoxy such ascarbomethoxy, carboethoxy, carbopropoxy or the like, or2-(alkanoyloxylower alkoxy)lower alkyl (with up to about 14 carbons inthe alkanoyl group) such as '2-(decanoyloxyethoxy) ethyl or the like.

Illustrative of the heterocyclic radicals represented by are thefollowing: piperidino; (lower alkyl)piperidino [e.g., 2-, 3-, or4-(lower alkyl)piperidino]; di(lower alkyl)piperidino [e.g., 2,4-, 2,5-,3,S-di(lower a1kyl)piperidino]; (lower alkoxy)piperidino; [e.g.,Z-methoxypiperidino or 3-methoxypiperidino]; hydroxypiperidino [e.g., 2-hydroxyor 4-hydroxypiperidino]; pyrrolidino; (lower alkyl)pyrrolidino[e.g., 3-methylpyrrolidino]; di(lower alkyl)pyrrolidino [e.g.,3,4-dimethylpyrrolidino]; (lower alkoxy)pyrrolidino [e.g.,Z-methoxypyrrolidino]; morpholino; (lower alkyl)morpholino [e.g.,3-methylmorpholino]; di(lower alkyl)morpholino [e.g.,3,5-dimethylmorpholino]; (lower alkoxy)morpholino [e.g.,2-methoxymorpholino]; thiamorpholino; (lower alkyl)thiamorpholino [e.g.,3-methylthiamorpholino]; di(lower alkyl)thiamorpholino [e.g.,3,5-dimethylthiamorpholino]; v(lower alkoxy)thiamorpholino [e.g.,3-methoxythiamorpholino]; piperazino; (lower alkyl)piperazino [e.g., N-methylpiperazino]; di(lower a1kyl)piperazino [e.g.,2,5-dimethylpiperazino or 2,6-dimethylpiperazino]; (loweralkoxy)piperazino [e.g., 2-methoxypiperazino]; (hydroxy-lower alkyl)piperazino [e.g., N -(2 hydroxyethyDpiperazino]; (alkanoyloxy-loweralkyl)piperazino wherein the alkanoyloxy group has up to 14 carbons;[e.g., N -(2-heptanoyloxyethyl)piperazino or N-(2-dodecanoyloxyethyl)piperazino]; (hydroxy-lower alkoxyloweralkyl)piperazino [e.g., N (2-hydroxyethoxyethyl)piperazino];-'(carbo-lower alkoxy) piperazino [e.g., N -(carbomethoxy-,carboethoxy-, or carbopropyl)piperazino]; homopiperazino; or N-(2-hydroxyethyl)homopiperazino.

The particularly preferred compounds are those wherein R is hydrogen,3-(4-methy1-1-piperazinyl)propyl, allyl or phenethyl.

The compounds of Formula N form acid addition salts with variousinorganic and organic acids. These salts frequently provide convenientmeans for separating the product from the reaction mixture in which itis produced or from the solvent in which it is produced or from thesolvent in which it is extracted in view of their insolubility invarious media. Thus the product may be precipitated in the form of aninsoluble salt and converted, by conventional techniques, to the freebase or to another salt if desired.

Illustrative salts include the hydrohalides, such as hydrochloride,hydrobromide and hydroiodide, especially the first two, other mineralacid salts such as phosphate, sulfate, nitrate, etc., organic aci sa ssu h as oxalate,

tartrate, malate, maleate, citrate, camphorsulfonate, methanesulfonate,benzenesulfonate, toluenesulfonate, salicylate, benzoate, ascorbate,mandelate, pamoate or the like.

The compounds of Formula 1V and their physiological ly acceptable saltsare useful as antiviral, cardiovascular or antiinflammatory agents totreat or alleviate the symptoms in various warm blood animals. While allof the class in general exhibits these properties, those compoundswherein R is a lower alkenyl, cycloalkyl-lower alkyl or aralkyl grouphave antiviral activity as the predominant property; those compoundswherein R is have cardiovascular activity as the predominant propertyand those compounds wherein R is (CH COOH have antiiniflammatoryactivity as the predominant property.

As anti-inflammatory agents, the compounds of this invention may be usedtopically in lieu of and in the same manner as cortisone in thetreatment of acute inflammatory and allergic conditions of the eye, skinor mucosa, e.g., as suspension, ointment or cream containing about 0.1to about 2.5%, by weight, of a compound of Formula IV or salt thereof.In the rabbit, for example, a 1% ointment is applied to the skin area 3to 4 times daily.

To arrest cardiac arrhythmias, the compounds of this invention areincorporated in conventional oral or parenteral dosage forms foradministration in single or divided doses of about 4 to 50 mg./kg./day,preferably about 5 to 20 mg./kg./day 2 to 4 times daily. For example, inmice about 10 mg./kg. orally are used.

About 4 to 50 mg./kg./day, preferably about 5 to 25 mg./kg./day, usedorally or parenterally in two to six divided doses, may be used tocombat influenza virus such as A-PR8 or hepatic virus such as MHV Forexample, about 5 to 15 mg./kg., in an injectable vehicle, may be usedtwo to four times daily against influenza virus in mice.

The compounds of Formula IV or their physiologically acceptable acidaddition salts may be administered by incorporation in conventionalforms such as tablets, capsules, elixirs or suspensions for oraladministration, in sterile solution or suspension for parenteraladministration, or in ointment, cream or lotion for topical use. Thedosage form is formulated according to conventional practice includingcarriers, adjuvants, excipients, lubricants, stabilizers, etc. asrequired. About 0.1 to about by weight of the active substance may beincluded. For oral administration a tablet or gelatin capsule containingabout 5 to about percent by weight of active material, e.g., about 5 to500 mg., and the remainder conventional adjuvants may be made up. Anaqueous suspension or syrup containing about 0.5 to 10 percent of activematerial may also be used. Sterile injectable solutions or suspensionsmay be made up containing about 0.5 to 25%, preferably about 5 to 10percent, by weight of active substance in an aqueous vehicle such assterile water for injection, saline or the like, or in an oil such as avegetable oil like peanut oil, sesame oil or the like. For topical use,an ointment or cream containing about 0.1 to 2.5%, by weight of activesubstance in cream or ointment base as found in a standard pharmacy textsuch as Remingtons Practice of Pharmacy may be used.

To produce the new compounds of this invention 1- hydroxyadamantane istreated with concentrated sulfuric acid to obtain Z-adamantanone. Thelatter is reacted with hydroxylamine hydrochloride or sulfate to give2-adamantanone oxime. The oxime of Z-adamantanone, by Beckmannrearrangement with excess polyphosphoric acid, phosphorous pentachlorideor the like, at -130 C., yields 4-azatricyclo[4.3.1.1 ]undecan-5-one ofFormula I.

Reduction of the lactam of Formula I, e.g., by refluxing with lithiumaluminum hydride in an inert solvent like ether, tetrahydrofuran,dimethoxyethane or the like, gives 4-azatricyclo[4.3.1.1 ]undecane ofFormula II. The latter, when alkylated with a compound Rhal yields the4-azatricyclo[4.3.1.1 ]undecane derivatives of Formula IV.

If, however, the lactam of Formula I is first alkylated with a compoundR-hal, the 4-azatricyclo[4.3.1.1 undecan-S-one derivatives of FormulaIII are obtained and these in turn may be reduced with lithium aluminumhydride as described above to obtain by this alternative route the samecompounds of Formula IV.

The following examples are illustrative of the invention. Alltemperatures are on the centigrade scale.

EXAMPLE 1 Oxime of Z-adamantanone To a cooled solution of 8.5 gm. (0.05mole) of 2-adamantanone, 6.2 gm. (0.09 mole) ofhydroxyylamine-hydrochloride and 16 ml. of water, 11.2 gm. (0.28 mole)of sodium hydroxide are added with stirring. The mixture is refluxed forminutes. After cooling the contents are poured onto 300 ml. of 1 N HCl.The precipitate which forms is filtered, giving 5.3 gm. (57%) of theoxime of Z-adamantanone as white crystals; M. P. 160-164 0.,

W301 1672 cm.- (C=N EXAMPLE 2 4-azatricyclo [4.3 .1.1 ]undecan-5- Amanually stirred mixture of 3 gm. (0.018 mole) of the oxime ofZ-adamantanone and 90 gm. of polyphosphoric acid is placed in an oilbath preheated to 140 C. The temperature of the mixture is held between120- 130 C. for 10 minutes. At the end of the period, the dark brownsolution is cooled and treated with 500 ml. of water. The mixture isextracted with 500 ml. of chloroform, dried (MgSO and evaporated, giving1.4 gm. of crude white solid. Sublimation of the present gives 1.17 gm.(39%) of white crystals of 4-azatricyclo[4.3.1.1 undecan-S-one, meltingat 270 0.,

33;, 1650 cm? (0:0), TCDC13 7.5-8.4 (adamantyl protons), 6.4-7.5 (NH andmethine hydrogen adjacent to carbonyl).

Analysis.Calcd. for C H NO (percent): C, 72.69; H. 9.15; N, 8.48. Found(percent): C, 72.98; H, 9.00; N, 8.43.

EXAMPLE 3 4- 3- (4-methyll-piperazinyl) propyl] -5-azatricyclo[4.3.1.1]undecan-5-one To a well stirred solution of 2.4 gm. (0.02 mole) of4-azatricyclo[4.3.1.1 ]undecan-5-one in 300 ml. of toluene, 3.2 gm. ofpowdered sodium hydroxide are added. After 5 minutes of vigorousstirring, 12 gm. of 1-(3-bromopropyl)-4-methylpiperazine dihydrobromideare added and the mixture heated for minutes on a steam bath. Thereaction mixture is cooled and stirred with 50 ml. of cold water. Thetoluene layer is separated, washed with 2X 50 ml. of water and extractedwith 3x 100 ml. of 5 N HCl. The acid extracts are combined, washed with100 ml. of ether, cooled and made basic with 2 N NaOH. The free base isextracted with 3x 250 ml. of chloroform, dried (MgSO and evaporated invacuo to give 4-[3-(4-methyl 1 piperazinyl)propyl] 5 azatricyclo-[4.3.1.1 ]undecan-5-one.

EXAMPLE 4 4-[3-(4-methyl-l-piperazinyDpropyl]- 5-azatricyclo[4.3.1.1undecane To a cooled suspension of 1.5 gm. of lithium aluminum hydridein 50 ml. of tetrahydrofuran, 1.5 gm. (0.01 mole) of5-[3-(4-methyl-1-piperazinyl)propyl]-5-azatricyclo[4.3.1.1]undecan-5-one in 50 ml. of tetrahydrofuran are added dropwise withstirring. The mixture is refluxed overnight. Excess lithium aluminumhydride is decomposed by the cautious addition of water to the cooledmixture. The gelatinous precipitate becomes granular after the additionof 30 ml. of 10% sodium hydroxide. The precipitate is filtered off andtetrahydrofuran is removed in vacuo from the filtrate. The residualmaterial is extracted with 3 50 ml. of ether. The ether extract is driedover magnesium sulfate and the product, 4-[3-(4-methyl 1piperazinyl)propyl] 5 azatricyclo- [4.3.1.1 ]undecane, is isolated byevaporation of the ether solution in vacuo.

EXAMPLE 5 4-azatricyclo [4.3.1.1 ]undecane hydrochloride To a cooledsuspension of 0.37 gm. (0.01 mole) of lithium aluminum hydride in 10 ml.of dry tetrahydrofuran, 0.5 gm. (0.003 mole) of 4-azatricyclo[4.3.1.1undecan-S-one in 10 ml. of dry tetrahydrofuran are added dropwise withstirring. The mixture is refluxed overnight. Excess lithium aluminumhydride is decomposed by the cautious addition of 10 ml. of water to thecooled mixture. The gelatinous precipitate becomes granular after theaddition of 10 ml.of 10% NaOH. The precipitate is filtered and thetetrahydrofuran is removed from the filtrate. The residual material isextracted three times with 50 ml. of ether. The extract containing crude4-azatricyclo[4.3.l.1 ]undecane is dried (MgSO and a solution of HCl inether is added until precipitation is complete. The crude salt, 0.300gm. (53%) is crystallized from alcohol-ether to give 0.130 gm. (23%) ofwhite crystalline 4-azatricyc1o[4.3.1.1 ]undecane hydrochloride, M.P.above 270";

max.

Nuiol 2600-2440- (-NH2) 1610 crnr (rn.) (NH2+),

EXAMPLE 6 4-allyl-5-azatricyclo[4.3.1.1 ]undecane To a well stirredsolution of 1.2 gm. (0.01 mole) of allyl bromide in 50 ml. of benzene, asolution of 1.5 gm. (0.01 mole) of 4-azatricyclo[4.3.l.1 ]undecane in 50ml. of benzene is added dropwise. The mixture is refluxed 1 hr., cooled,and 1 gm. of acetic anhydride is added. The mixture is refluxed anadditional 2 hrs., cooled, poured into ice water and acidified withacetic acid. The layers are separated and the aqueous layer is extractedwith ether. The acidic aqueous layer is made basic with NaOH, andextracted with chloroform. The chloroform extract is washed with water,dried over magnesium sulfate, filtered and the solvent evaporated togive 5-allyl-4- azatricyclo[4.3.1.1 ]undecane.

The following additional products of Formulas IH and 1V may be obtainedby substituting in the procedure of Example 3 for the1-(3-bromopropyl)-4-methylpiperazine the compound listed in the middlecolumn below. By otherwise following the procedure of that example, theproduct of Formula III, wherein R is the group listed in the right handcolumn below, is obtained. Then by utilizing that product in theprocedure of Example 4, the product of Formula IV, wherein R is the samegroup listed in the right hand column, is obtained. Any acid additionsalt may be obtained by the procedure of Example 5 utilizinghydrochloric acid or another inorganic or organic acid.

Example Reaetant R OH; CH:

35 Cl-(CH hNHCH; -(CHg)4NHCH: 36 ClCH(CHa)CHzN(CHa)z -CH(CH3) CHzN(CH3):37 C1(CH:):NH2 "'(CH2)3NHI 38 CH1 $HI Cl-H-CH; GHCH1 39 Cl(OHg) CH=CH;-(CHz)zCH=CH1 40 Cl-CH: GH: 41 C1C2H5 --C2 s What is claimed is: 2. Acompound of the formula 1. A compound of the formula H:

0 25 HO H0 crr L H2O g N-R H2 CH; (EH/1 C2 30 H HC HzC (JH wherein R is3-(4-methy1- 1 -piperazinyl)propy1, and LE J E physiologicallyacceptable acid-addition salts thereof. H CH CH n 1 References Cited g35 Narayanan et al., C. A. 72, 90334a (1970).

wherein R is (4-lower alkyl-l-piperazinyDlower alkyl, and

physiologically acceptable acid-addition salts thereof.

ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner US. 01.X.-R.

260--239 B, 239.3, 247.2 B, 247.5 B, 247.7 A, 293.59, 326.3, 326.81;424-232, 244, 246, 248, 250, 267, 274

- UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION t n N I3,763,165 Dated October 2, 1973 I )Venkatachala Lakshmi Naravanan andLinda Louise Setescak It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

C olumn 1, line 3, "UNDECAN" should read--UNDECANE--; line 5, .1

"Lakshma Naraynan" should read-Lakshmi Narayanan-. Column 2, line 24,"represents" should read-represe nt-; line 38, "hydroxyl" shouldread--hydroxy-. Column 3, line 34, "2-" should read-- 3- line 57,"carbopropyl)" should read-- carbopropoxy)--. Column 5, line 52, "4-[3-"should read-- 5-[3- same line, "5-aza-" should read- 4-azaline 67,"4-[3" should read-- 5-[3- same line, "5azatricyclo" should read4-azatricycloline 71, "4-[3-" should read-- 5-[3- line 72,"S-azatricyclo" should read-- 4-azatricyclo Column 6, line 1, "8,3"should read-"3,8 line ll, "4[3-" should read-- 5-[3- same line,"5azaltricyclo-" should read-- 4-azatricycloline 49, 4--allyl5-" shouldread-5allyl-4- Signed and sealed this 19th day of February 19714..

(SEAL) v Attest: V v I I .7 v

MARSHALL DANN Commissioner of Patents EDWARD M.FLETCHER,JR. AttestingOfficer

